JP2008534629A - Oral delivery system - Google Patents

Abstract

An oral delivery system is provided that can be mixed in a normal dry powder process and can be compressed using a standard tablet making machine.
(A) an effective amount of one or more active ingredients; (b) one or more molecular weights of 1000 to 8000 in an amount sufficient to provide the hardness and time required for dissolution of the matrix. Polyethylene glycol or derivatives thereof; (c) one or more suspending agents of 0.05 to 2% by weight of the total matrix; (d) one or more flows of 0.05 to 2% by weight of the total matrix. An oral delivery system comprising: an agent; and (e) one or more sweeteners of 0.05-2% by weight of the total matrix.
[Selection figure] None

Description

  The present invention relates to an oral delivery system that provides improved therapeutic drug delivery. In particular, the present invention relates to a preparation for oral administration. The present invention further provides a simpler and more economical method of producing dosage formulations that can deliver one or more active ingredients through the oral membrane.

  Although this document refers to or discusses documents, acts, or knowledge items, this reference or discussion is known that the documents, acts, or knowledge items, or combinations thereof, are publicly available on the priority date. It is not an admission that it is known to be part of a well-known knowledge; or that the present specification relates to an attempt to solve the problem concerned.

  The ability to efficiently deliver therapeutic agents to animals, particularly humans, often depends on recipient compliance. Compliance is also often tied to or associated with the formulation used to deliver the agent. The formulation provided also depends on ease of manufacture.

  In addition to this, the formulation itself is often important for the efficacy of the drug being delivered. This is especially true for the delivery of analgesics such as paracetamol. One of the rate limiting steps in paracetamol delivery to the bloodstream is the gastric emptying rate. Various formulations have been proposed that provide paracetamol at alkaline pH.

  There is a continuing need to develop more improved drug delivery formulations that deliver therapeutic agents quickly and efficiently without inducing unwanted side effects.

  The main purpose of the drug delivery system is to obtain specific biological effects at the target site of action while minimizing side effects. It is taught that the biological activity of a pharmaceutical is not optimal if it does not have the proper physiochemical properties that allow the release of the biologically active form. To that end, improved drug delivery strategies focus on altering the physicochemical properties of active drugs, including stability, solubility, and dispersibility.

Lozenges In the 1800s, lozenges were widely used to treat mouth and throat infections. These are small, square, mildly medicinal solids that dissolve in the mouth. The finished troche is dispensed into a plastic calibrated mold and contains accurate and precise dosage units. In the UK they are called lozenges, in the United States they are called lozenges, in France they are called tablets, and in Germany they are called pastillens. Lozenges dissolve slowly in the oral cavity and most of the active ingredient is absorbed by the soft inner layer of the cheek. In this case, the bloodstream carries hormones to other parts of the body, similar to needle injection.

  Troche first appeared in the Edinburgh Pharmacopoeia in 1841, followed by the British Pharmacopoeia in 1864. In the 1800s, making lozenges was an artistic task and required a lot of work experience. The equipment needed to make the troches is a smooth marble plank, a stick, a troche cutter, a pallet knife, a brush with long soft badger hair, a linen cloth, and a tray for troches to mix them. there were.

  Today with computers, marble slabs, wooden trays, brushes, etc. are complex electric mixers, flavored poly-glycol substrates, precision electronic balances (measuring milligram doses), and finished It has been replaced by small electric hotplates that make the troches an accurate and precise dosage form. The finished troches are dispensed into plastic calibrated molds. A wide range of flavoring lozenges are available to help obtain compliance from the most difficult patients.

  A troche provides a means of delivering small doses of specialty pharmaceuticals directly into the bloodstream. Many drugs today can be used in the form of lozenges, both crude and synthetic, to obtain a rapid onset of action and avoid absorption into the normal bloodstream, thus bypassing the liver can do. This reduces the burden on the liver and is particularly beneficial for hepatotoxic drugs.

  Today, lozenges are mainly used for hormone replacement therapy because it is easy to change the ingredients for each prescription, and absorption in the cheek does not involve metabolism in the stomach. The lozenges can also be mixed such that each individual lozenge contains a small dose of a combination of various natural hormones. For example, the troches can be mixed to contain any identity natural hormones such as estrogen, progesterone, testosterone, and a mixture of DHEA in any possible dose. This combination is used to treat menopausal symptoms. For male menopause, the combination of testosterone and DHEA is most commonly used. A lozenge containing only natural progesterone is useful for premenstrual syndrome and can be administered late in the menstrual cycle to reduce depression, migraine, nausea, and essentially all PMT symptoms that occur in the early menstrual cycle.

  They can also be used in anesthetics, antibiotics, analgesics, antibacterial agents, antitussives, demulcents, and other combinations of pharmaceuticals.

  Lozenges are thought to be absorbed directly into the buccal circulation and are therefore marketed as a way to administer drugs that bypass the first-pass metabolism of the stomach and liver. This is said to reduce the stress on the liver and as a result more beneficial for the patient. In practice, over 50% of the lozenge dosage (up to 70%) is actually swallowed during normal salivary secretion, they encounter gastric acid and undergo first-pass metabolism, but the rest It is absorbed by the buccal mucosa (Non-patent Document 1). Since only 30-50% of the dose is absorbed from the mucosal layer in the oral cavity, the decrease in first pass metabolism in the liver when compared to capsules is considered to be negligible. Regardless of whether it is the oral mucosa or the gastrointestinal tract, the finally absorbed hormone eventually passes through the liver through the normal circulation at some stage, so there is no true liver saving effect. Clinical experience shows that the dose required for troches is in the same range as that required for capsules and the overall “total load” on the body is about the same, so in this sense also a true liver-saving effect Indicates that it cannot be obtained. Creams, on the other hand, require lower doses than lozenges and capsules, actually bypassing the first pass metabolism of the stomach and liver, and are therefore the only way to actually reduce the overall burden on the liver.

  Hormones with low oral bioavailability (10-15% bioavailability) such as progesterone and testosterone can be good candidates for buccal administration. If successful, the dose for buccal administration should be close to a normal physiological dose, for example 20-40 mg per day as seen in creams with progesterone. Clinical experience has shown that the dosage of progesterone required for troches is usually between 200 and 400 mg per day, which indicates that much of the dosage is not absorbed by the oral mucosa. Supporting the proof that many are swallowed. Perhaps oral mucosal patches provide better absorption properties than lozenges, but are not currently available. In addition, for hormones such as estrogens and DHEA that already have good oral bioavailability (greater than 90%) there is no real advantage to using buccal mucosal administration over oral administration.

  Troches also have poor pharmacokinetic parameters. This means that the serum level of hormones after taking troches varies greatly. Immediately after taking a lozenge, serum hormone levels rise rapidly, sometimes rise to very high levels, and then fall rapidly to low levels within 4-5 hours. Therefore, it is necessary to administer at least twice a day, or to obtain the best results, it is necessary to administer 3-4 times a day to maintain an appropriate level for an extended period of time. In the schedule, compliance is a major issue. This large variation in hormone levels is not an ideal situation. Creams and sustained release capsules release hormones more slowly in the blood and achieve stable serum levels for longer periods of time, so that generally only a single dose is needed.

Lozenges are made from two types of substrates, both of which have some drawbacks:
Polyethylene glycol (PEG) -PEG substrates are well known to cause allergic and hypersensitivity reactions and can cause inflammation of the oral mucosa. In addition, PEG-based materials may contain small amounts of dioxins that have been shown to cause cancer; and • gelatin—together with hydrophobic (lipophilic) particles such as bioidentical hormones It is a hydrophilic (water-preferred) base material that forms aggregates. This agglomeration of the particles further reduces mucosal absorption, increases swallowing volume, and the hormone cannot be evenly dispersed in the slurry, causing significant fluctuations in dosage between manufactured troches.

  In short, lozenges are currently widely used to administer bioidentical hormones to women, but they have many drawbacks and are not considered the best option. Transdermal creams are considered the first option because they require lower doses than troches and capsules and because they are the only route of administration that truly bypasses the stomach and first-pass metabolism. It is done. They provide better release parameters and provide stable serum levels without the large fluctuations found in lozenges. They can be administered once a day, and are therefore more convenient and dosage adjustments are very simple, and ultimately the cost of a standard formulation is very low, about $ 30 / month. If the cream is deemed inappropriate, the second option would be a sustained release capsule. These capsules provide better release characteristics compared to lozenges and can be administered only once a day, can be administered quickly and have no bitterness. Lozenges are suitable for patients whose cream is inappropriate and malabsorption syndrome develops, resulting in inadequate oral administration.

  There is thus a need for improved formulations for sublingual or buccal delivery of agents to patients.

Bisphosphonates A group of drugs that are particularly beneficial in a range of situations are bisphosphonates. Osteoporosis is one of the conditions in which the bisphosphonate drugs alendenate and risedronate are often prescribed.

  Osteoporosis and selected bone resorption conditions are important medical disorders that afflict millions of victims worldwide. Examples of other bone resorption conditions include other diseases or physiological conditions in which bone mineral density is actually decreased or at risk of loss, as well as menopause, hypogonadism, osteogenesis imperfecta, Paget's disease, bone marrow Deviated from the normal reference range as a result of diseases or physiological conditions such as neoplastic bone disease, cancer metastasis to bone, primary hyperthyroidism, fibrous osteodysplasia, and malignant hypercalcemia Osteolysis is mentioned.

  For example, an estimated 44 million people over the age of 50 in the United States currently have osteoporosis or low bone mass. This number may exceed 61 million in 2020 (Non-Patent Document 2).

  Osteoporosis patients must receive long-term medication with anti-resorptive drugs to prevent further bone loss. As described above, alendronate and risedronate are generally prescribed as anti-absorbents.

  However, both drugs are poorly absorbed (about 1% of the ingested dose) and this rate will be further reduced if the drug is not taken as directed. Violation of compliance is a common problem in current administration protocols due to gastrointestinal irritation of bisphosphonate, which often causes nausea and even vomiting in some patients.

  Bisphosphonates are also often prescribed in connection with hormone replacement therapy (HRT) to counter the effects of decreased sex hormone production before and after menopause. Sex hormone replacement generally uses the gastrointestinal route of administration, in which a significant amount of the hormone is degraded by the digestive environment before being absorbed. For that reason, in order to ensure that the therapeutic dose reaches the bloodstream, more of the hormone must be used than is required when manufacturing the oral hormone dosage form.

  Many women's menopausal specific HRT regimens have been devised, but their clinical success rates vary. Most of these therapies use natural 17-β-estradiol, conjugated equine estrogen, or other conjugated estrogens in combination with synthetic progesterone such as nor-ethisterone, levonorgestrel, and didrogesterolone. Based on. Such a combination of therapeutics is highly effective in controlling symptoms, but again, patient compliance is often a limiting factor in overall clinical efficiency. Side effects such as gastrointestinal irritation and bloating are unacceptable for many patients.

Poor patient compliance is a major obstacle to completing a prescription regimen and is the cause of suboptimal clinical outcomes. Thus, there is a need to develop drug delivery formulations that reduce side effects that affect patient compliance.
Int J Pharm Comp. 4,414-420,2000 National Osteoporation Foundation America's Bone Health: The State of Osteoporosis and Low Bone Mass, 2002

  The present invention provides an oral delivery system that provides improved bioavailability of active ingredients. The buccal delivery system of the present invention avoids the effects of the liver in “first pass metabolism” and thus can increase the delivery of the active ingredient, sometimes up to over 85%. As used herein, the term “oral (chum)” is used in its broadest sense and refers to the entire mouth, including the sublingual.

  Since the oral delivery system of the present invention provides improved bioavailability, the present invention can be used to reduce the active ingredient used to produce the dosage form.

  In addition, the oral delivery system of the present invention can reduce the severity of gastrointestinal side effects of certain agents, such as digestive disorders, pain, nausea, vomiting, constipation, convulsions, diarrhea, and belly. it can.

  The present invention is also more convenient and more economical because it can be made using a dry manufacturing process where all active ingredients are mixed into a normal dry powder and compressed using a standard tablet making machine. An oral delivery system that can be manufactured is also provided. Such dry formulations can be produced in commercial numbers and provided in normal blister packaging. The active ingredients and excipients are similar to those used in prior art lozenges, however the excipients have been modified, costly and time-consuming specialized wet formulation factories and equipment, and prior art Manual processing required for troches (soft gel products) is not required.

According to a first aspect of the invention, an oral delivery system that can be mixed in a normal dry powder process and compressed using a standard tablet making machine:
(A) an effective amount of one or more active ingredients;
(B) one or more polyethylene glycols of molecular weight 1000-8000 or derivatives thereof in an amount sufficient to provide the hardness and time necessary for dissolution of the matrix;
(C) one or more suspending agents of 0.05 to 2% by weight of the total matrix;
(D) one or more fluidizing agents of 0.05-2% by weight of the total matrix; and (e) a matrix of sweeteners of 0.05-2% by weight of the total matrix. An oral delivery system is provided.

  Effective amounts of the active ingredients are typically in amounts up to about 60% by weight of the total matrix.

  The matrix can release the active ingredient from within seconds to hours of application, depending on the desired release profile. Typically, the active ingredient can be released from the matrix within at least 2 hours, preferably within 1 hour, and even more preferably within 40 minutes after application to one or more membranes in the oral cavity. Most preferably, dissolution occurs within 12-15 minutes. In the case of emergency treatment, preferably the matrix should dissolve within 5 minutes of application.

  As used herein, the term “oral delivery system” refers to a delivery system in which an active ingredient is absorbed across one or more membranes in the mouth including the oral mucosa, buccal gingiva, lingual mucosa, sublingual membrane, and soft palate. Point to. The term encompasses all suitable dosage forms that can be manufactured using conventional dry powder processes and that can be compressed using standard tablet machines.

  “Active ingredient” refers to therapeutic or prophylactic active ingredients, drugs, prodrugs, complex drugs, intermediate drugs, diagnostic drugs, enzymes, pharmaceuticals, plant extracts, herbal mixtures, phytochemicals, proteins, antibodies, nanobodies, antibodies Fragments, antibodies intended for therapeutics of enzyme prodrugs (ADEPT), bioactive compounds, nutritional supplements, or food supplements.

  As used herein, the term “matrix” includes one or more dissolved or dispersed active ingredients, together with extraneous materials that control the rate of surrounding them, and the active ingredients when the matrix touches a wet diffusible membrane directly Refers to a solid or semi-solid monolithic material that releases. Solid or semi-solid monolithic substances are within the range known in the art of pharmaceutical delivery to emulsify, solubilize, complex or deliver biologically active lipophilic or hydrophilic compounds across membranes. Substances can be included.

  Those skilled in the art will know which polyethylene glycol (PEG) is suitable to provide the desired pharmacokinetics for the delivery system. For example, the choice of PEG will depend on whether zero order or first order release is desired. In a particularly preferred embodiment, the substrate is PEG 1450.

  Polyethylene glycol can be used in the form of PEG-fatty acid esters with surface active properties. Examples of suitable PEG-fatty acid esters include PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG- 20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl stearate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl olea PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate / caprylate glyceride, PEG-8 coupler / caprylate glyceride, polyglyceryl-10 laurate PEG-30 cholesterol, PEG-25 phytosterol, PEG-30 soybean sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, PEG-1450, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol series, PEG 15-100 octylphenol series, poloxamer, and mixtures thereof.

  One skilled in the art will appreciate that the amount of suspending agent is sufficient to improve the texture and consistency of the delivery system. Suitable examples of such suspending agents are rubber-producing plants such as those of tetragonolobus, Acacia glaucophylla, Acacia abyssinica, Acacia ilotica, Acacia gummifera, and Acacia arabica. Other suitable suspending agents include silica gel and Kollidon, Cremophor, Kollicoat, Sultol, and ludipless.

  One skilled in the art will understand that a fluidizing agent (also known as a lubricant) is present in an amount effective to prevent adhesion, particularly to prevent adhesion during the manufacturing process. A preferred example of the fluidizing agent is magnesium stearate.

  The buccal delivery system includes an amount of sweetener sufficient to improve the sensory stimulation properties of the dosage form. Examples of suitable sweeteners include sucrose, sucralose; zinc gluconate; ethyl maltitol; glycine; acesulfame-K; aspartame; saccharin; fructose; xylitol; honey; corn syrup, golden syrup, misri Examples include licorice; glycerizine; dextrose; sodium gluconate; stevia powder; glucono delta-lactone; ethyl vanillin; vanillin; and normal and enhanced sweeteners or syrups, or salts thereof. Preferably, a strong sweetener selected from the group consisting of aspartame, sucralose, and acesulfame-K is used.

In another aspect, the present invention provides a method for producing a dosage formulation capable of delivering one or more active ingredients across one or more membranes in the oral cavity, comprising:
(A) (i) one or more effective amounts of active ingredients;
(Ii) one or more polyethylene glycols or derivatives thereof having a molecular weight of 1000 to 8000 and sufficient to provide the hardness and time required for dissolution of the matrix;
(Iii) one or more suspending agents of 0.05 to 2% by weight of the total matrix;
(Iv) mixing one or more fluidizing agents of 0.05-2% by weight of the total matrix; and (v) one or more sweeteners of 0.05-2% by weight of the total matrix. Preparing the matrix by:
(B) compressing the matrix into a tablet shape suitable for administration to one or more membranes in the oral cavity;
A method is provided wherein the ratio of active ingredient to excipient is such that it allows dissolution and absorption of the active ingredient within the desired time.

  Examples of suitable active ingredients include anti-infectives (antibiotics), eye, ear, nose, and pharyngeal preparations, anti-neoplastics including antibodies, nanobodies, antibody fragments, antibodies for therapeutic enzyme prodrugs (ADEPT) ), Gastrointestinal drugs, respiratory drugs, joint drugs, blood formation and coagulation drugs, diagnostics, photosensitizers (eg, agents that stimulate porphyrin and natural porphyrin production), statins, naproxins, indole-3-acetic acid, hormones And synthetic substrates, cardiovascular drugs, skin and mucosal regulators, NSAIDs, analgesics, muscle spasms, anti-inflammatory drugs, central nervous system drugs, supplements, diabetes drugs, and electrolyte and water balance agents, mixtures thereof, and These include, but are not limited to, prodrugs, drug conjugates, intermediates, enzymes, vitamins, and protein conjugates.

  Other active ingredients include, for example, insulin, triamcinolone, testosterone, levonorgesterol, estradiol, phytoestrogen, estrone, dexamethasone, ethinodiol, prednisone, desogestrel, cryptoterone, norethindrone, megestrol, hydrocortisone, danazol, cortisone acetate , Avian, Nandrolone, Fluoxymesterone, Fludrocortisone, Fluoxymesterone, Dexamethasone, Revola, Fludrocortisone, Low-Ogestrel, Methylprednisolone, Necon, Levonorgestrel, Estropipeto, Levoxil, Methimazole, Profilthiouracil・ Desmopressin, Prednisolone, Orgestrel, Norethindrone, Tori Includes mycinolone trivora zovia guestden, alphacalcidol, 1,25-dihydroxyvitamin D3, clomiphene, finasteride, and tibolone, or biologically related intermediates thereof, or combinations thereof Examples include hormones of natural or synthetic origin selected from the group of hormones.

  In one preferred embodiment, the active ingredient is a bisphosphonic acid or bisphosphonate salt useful in the treatment of bone resorption conditions. Reference to “bisphosphonic acid” includes one or more acids and pharmaceutically acceptable salts and derivatives thereof. This term can be used to refer to salt forms such as “bisphosphonates”. Preferred bisphosphonic acids and their salts include groups comprising alendronate, etidronate, pamidronate, tiludronate, and risedronate compounds. Even more preferably, the bisphosphonate is an alendronate selected from the group comprising anhydrous alendronate or a hydrogenated alendronate salt such as alendronate sodium.

  The oral delivery system of the present invention can contain two or more active ingredients. The active ingredients can be released at the same time, ie simultaneously or at different rates. A preferred combination is a combination of one or more bisphosphonic acids (or salts thereof) with one or more hormones used in hormone replacement therapy such as estradiol, progesterone, testosterone, and / or dehydroepiandrosterone (DHEA). is there.

  Efficient drug delivery techniques also require that the drug be soluble in an aqueous biological medium and in a form suitable to allow the transfer of individual drug molecules or very small aggregates of drug molecules. . Oral delivery systems include pharmaceutically acceptable carriers such as binders, flavoring agents, colorants, solubility enhancers, disintegrants, extenders, proteins, cofactors, emulsifiers, and solubilizing or complexing agents and / or Alternatively, one or more excipients may be further included, but the present invention is not limited to these. In preferred embodiments, these excipients will improve delivery of the active ingredient across the membrane. Suitable excipients are known to those skilled in the art. One typical example of a suitable emulsifier is tocopherol polyethylene glycol 1000 succinate (TPGS). Examples of complexing agents are compounds containing amine groups or other nitrogen functional groups such as amino acids containing amine functional groups, proteins, amine functional sterols and phospholipids. Suitable surfactants are amphiphilic, zwitterionic or cationic surfactants. Preferred complexing agents of this type include water-soluble cationic polymers having quaternary ammonium functional groups in the main chain of the polymer, and water-soluble cationic guar (jaguar gum).

  In a preferred embodiment, the oral delivery system includes a bound gelling agent such as hydroxypropylmethocellulose.

  In another aspect, the oral delivery system further includes a colorant that is a dye or pigment. Suitable colorants are well known in the art and include curcumin, carotenoids, sunset yellow, tartrazine, indigo dyes, quino-phthalene dyes, and triphenylmethane dyes.

  In a preferred embodiment, the oral delivery system further comprises a flavoring agent for improving sensory stimulation properties. Suitable flavoring agents are well known in the art and include almond oil; babasu oil; borage oil; black currant seed oil; rapeseed oil; castor oil; coconut oil; corn oil; cottonseed oil; Mustard oil; olive oil; palm oil; palm kernel oil; peanut oil; grape seed oil; safflower oil; sesame oil; shark liver oil; soy oil; sunflower oil; hydrogenated castor oil; hydrogenated coconut oil; Soybean oil; Hydrogenated vegetable oil; Hydrogenated cottonseed and castor oil; Partially hydrogenated soybean oil; Soybean oil; Glyceryl tricaproate; Glyceryl tricaprylate; Glyceryl tricaprate; Glyceryl triundecanoate; Glyceryl trioleate; Glyceryl trilinoleate; Glyce Glyceryl tricaprylate / caprate / laurate; glyceryl tricaprylate / caprate / linoleate; glyceryl tricaprylate / caprylate / stearate; saturated polyglycolized glycerides; linolenic acid glycerides; caprylic acid / Capric acid glycerides; modified triglycerides; fractionated triglycerides; safrole, vanillin, citric acid, maleic acid, and phosphoric acid, or salts and / or mixtures thereof.

  In another aspect, the oral dosage form is useful as a sustained release composition. The term “sustained release” (also referred to as “extended release”) refers to a drug formulation that gradually releases the drug over time, preferably but not necessarily, for a long period of time, making the drug level substantially constant. Used in the usual sense.

  The present invention also contemplates a method of treating and / or preventing a medical condition in mammals, particularly humans, by administering a drug using the delivery system of the invention.

  Various embodiments / aspects of the invention will now be described with reference to the drawings.

  Various aspects / aspects of the invention will now be described with reference to the following non-limiting examples.

Example 1-Comparative Example This example shows the process of troche preparation according to the prior art.

  The ingredients used for the 28 lozenges are shown in Table 1.

Component preparation-Calculate the required amount of active ingredient (for example, 30 lozenges of 200 mg progesterone require 6.0 g progesterone).
• Weigh the necessary components and place them on a clean, labeled weighing tray (eg 0.01 g).

Preparation of PEG substrate-Calculate the required substrate for the day (see Table 2) in a large 4 liter beaker, place on a hot plate and dissolve in the aqueous layer. The aqueous layer is set at 60 ° C.
When the base material A is dissolved, add other ingredients and stir using a spatula.

Making a troche • Place a 400 mL beaker on a scale and measure the tare. Add active ingredients. The PEG prepared above is then added until the total weight is 30.0 g.
・ Place the beaker on the hot plate and rotate the stirrer bar. Add the required flavors and rotate the mixture until all active ingredients are dissolved.
• Then pour the troche mixture into the mold, flatten with a spatula and dry.
Using a hair dryer, heat the top of the troche slowly until it begins to dissolve.
・ Use the edge of the mold to scrape off the excess part using a clean, bent spatula. Fill the holes with the surplus to make each lozenge a uniform dosage form. This will need to be repeated 2-3 times.
・ When uniform, heat the surface lightly to finish. Then clean the mold with a damp cloth.

Discussion It can be seen that this method is not suitable for commercial scale manufacturing. For commercial scale manufacturing, standard dry tablet manufacturing processes could be more preferably used.

Example 2
This example shows the production of LINGUET tablets according to the invention.

Release powders containing 5, 10, and 40 mg equivalents of the active ingredient alendronate sodium were mixed with the following excipients:
-PEG with a molecular weight of 1000-8000, depending on the hardness and time required for dissolution of the tablet
Magnesium stearate: 0.05-2% by weight
・ Collidon: 0.05-2% by weight
Stevia: 0.05-2% by weight
・ Active ingredient: Up to 60% by weight

  Standard dry mixing was performed for 60 minutes in a horizontal low energy mixer. The powder mixture was then mixed with PEG for 5 minutes and directly compressed using a TabletPress Inc bench top single press tablet punch.

  The dissolution time of these LINGUET tablets was in the range of 10-20 minutes, but the time required for complete dissolution after oral administration was slightly longer, 15-20 minutes.

Example 3
This example studies the bioavailability of a hormone replacement therapeutic active ingredient using the oral delivery system of the invention in a clinical trial at a hospital. This study was conducted with the approval of the hospital ethics committee.

  LINGUET tablets were produced to contain 17-β-estradiol (0.5 mg), progesterone (200 mg), testosterone (2.0 mg), and DHEA (10.0 mg). The excipients in LINGUET tablets consisted of silica gel, magnesium stearate, acacia, stevia, and polyethylene glycol, and wild berry flavoring. The LINGUET tablets used in this test were formulated as a single batch for this test using the inventive process described in Example 2 above. LINGUET tablets were provided by Richard Stenlake Compounding Charmist (Bondi Junction, Australia).

Study protocol The study was an open-label formal study of 6 postmenopausal women. Prior to study enrollment, subjects were given informed consent and medical and biochemical screening was performed. Subjects were generally in good health and had been at least one year after menopause. The age of the subjects is 45-60 years (average 56 years), average weight 69 kg (range, 64-76 kg), average height 166 cm (range 157-178 cm), and average body mass index 25.2 (range 23.4- 27.6).

  Subjects had no history of breast or uterine cancer, thrombosis, embolism, hypertension, diabetes, hyperlipidemia, obesity, or smokers. They also had no clinically significant abnormalities for routine biochemistry and hematology screening.

  Subjects discontinued herbal or alternative therapies as well as the HRT treatment prescribed to them at least 3 days before the first day of the study. Subjects went to the test center early in the morning on each test day after one night. An indwelling catheter was inserted into the forearm vein and a baseline blood sample was collected.

  On the first day, LINGUET half tablets were placed in the oral cavity (buccal and gingival) to dissolve. Subjects were instructed not to swallow the formulation. It took 40 minutes to dissolve the preparation in the oral cavity. At 45 minutes, subject rinsed mouth with water. Blood was drawn from the cannula periodically over 24 hours. Subject was discharged, but continued to take LINGUET half tablets twice daily for 2 weeks thereafter. Thereafter, the subjects went to the clinical trial center again and administered in the morning, and blood samples were collected regularly during the 12-hour administration interval.

  Blood samples were to be collected after a single dose at the following times: pre-dose (0), after single dose 0.25, 0.5, 0.75, 1.0, 1.5, 2 0.0, 3.0, 4.0, 6.0, 8.0, 12.0, 16.0, 20.0, and 24.0 hours, and pre-dose (0), 2-week dosing interval After (steady state), 0.25, 0.5, 0.75, 1.0, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 10.0, And 12.0 hours. Actual times were recorded and used for pharmacokinetic calculations.

  Saliva was collected for hormonal analysis according to the standardization method presented by the laboratory, Australian Reference Laboratories (Melbourne), and stored frozen (−20 ° C.) prior to shipping. Briefly, subjects rinsed their mouths thoroughly with water and waited 5-10 minutes for saliva to accumulate in their mouths. The subject then dispensed saliva directly into the collection tube.

  Saliva samples were collected at the following times for single dose evaluation: pre-dose (0), post-dose 1.0, 4.0, 8.0, 12.0, 16.0, and 24 hours. Eye. For steady state analysis, saliva was collected before dosing (0) and 1.0, 4.0, 8.0, and 12.0 hours after administration of LINGUET tablets.

Analytical Methods Hormone plasma concentrations were performed in hospital laboratories (Sydpath, St Vincent's Hospital, Sydney) using normal, validated radioimmunoassay techniques. The laboratory is an accredited pathology laboratory that participates in the national quality assurance program for hormone analysis.

  Hormone concentrations in saliva were performed at Analytical Reference Laboratories (Melbourne) using a commercially available radioimmunoassay that has been validated. This laboratory is also a certified pathology examination facility.

  DHEA was monitored as a sulfate metabolite (DHEAS), not as an administered hormone.

  Single and multiple doses of estradiol: LINGUET tablets showed very similar mean concentration-time profiles for estrogen in plasma. Substantial variability between subjects regarding concentration was revealed (Tables 3 and 4).

  Testosterone: Single and multiple doses of LINGUET tablets also show a substantially overlapping concentration-time profile for testosterone in plasma, with the concentration significantly increasing up to 4 hours, and then before treatment within about 8 hours Returned to the concentration. Absorption of this hormone was rapid compared to other hormones, with peak concentrations averaging 0.6 hours (Tables 3 and 4).

  Progesterone: Progesterone showed the highest dose accumulation by steady state (Table 3). This hormone elimination was considered biphasic, with a second peak after approximately 4 hours for both single and multiple doses. The concentration decreased within 5 hours to below that generally associated with biological activity in the uterine mucosa.

  Dehydroepiandrosterone (DHEA): A single dose of LINGUET1 / 2 tablet (5 mg DHEA) doubled the blood concentration of DHEAS for 5-10 hours and then returned to the pretreatment concentration within 24 hours. The variation between subjects was large (Tables 3 and 4).

Results and Discussion Concentration profiles of hormones in saliva: Prior to a single application of LINGUET tablets, the saliva concentrations of all four hormones appeared to be higher than the blood concentration. The concentration of estradiol and progesterone in saliva rose to a much higher level than that of blood after using LINGUET tablets. This increase was then maintained for 8-12 hours, suggesting that this large increase was not due solely to the hormone remaining in the oral cavity (see Table 5-Figure 6).

  It was found that in steady state the concentration of hormones in saliva increases to an unexpectedly high concentration. The saliva to plasma ratio varied significantly (see Table 5-Figure 6).

  Plasma hormones: Each of the four hormones, estradiol, progesterone, testosterone, and dehydroepiandrosterone (the latter being monitored as active sulfate) is easily absorbed from LINGUET tablets and is found in normal young women during menstruation The concentration reached. The peak concentration reached a very short time and returned to baseline between 4-8 hours after a single dose. The steady state profile was very similar to estrogen and testosterone, reflecting that their half-life was short relative to the dosing interval. In contrast, at steady state, progesterone maintained concentrations normally associated with the physiological and biological activities of normal young women. If this sustained concentration of progesterone has been shown to inhibit mitosis in the endometrium or cause secondary changes, this progesterone delivery route may be used to suppress postmenopausal symptoms. unknown.

  The advantage of the buccal delivery route is that it allows rapid absorption of hormones and achieves physiological concentrations. This formulation avoids the problems normally associated with transdermal applications, i.e., instability and poor absorption, while avoiding the first pass metabolism associated with oral administration.

  Table 5 shows the results of a single administration of LINGUET tablets on day 1 when the average hormone concentrations in blood and saliva were tested.

CONCLUSION LINGUET tablets containing the inventive oral delivery system delivered hormones into the blood through the oral cavity. The results obtained were described in Wren et al., “Pharmacokinetics of estradiol, progesterone, testosterone and testosterone and deuteroeprone after transcranial administration to postmenocr.

  The word “comprising” and word “comprising” terms used in the present description and in the claims limit the claimed invention and do not exclude variations and additions.

  Changes and modifications in the invention will be readily apparent to those skilled in the art. Such changes and modifications are intended to be within the scope of the present invention.

FIG. 1 is a schematic showing the results obtained for estradiol using the oral delivery system of the invention of Example 3. FIG. 2 is a schematic diagram showing the results obtained for progesterone using the oral delivery system of the invention of Example 3. FIG. 3 is a schematic diagram showing the results obtained for testosterone using the oral delivery system of the invention of Example 3. 4 is a schematic showing the results obtained for dehydroepiandrosterone-sulfate using the oral delivery system of the invention of Example 3. FIG. FIG. 5 is a schematic showing the results obtained for all hormones tested using the oral delivery system of the invention of Example 3. 6 is a table showing the results obtained for all hormones tested using the oral delivery system of the invention of Example 3. FIG.

Claims (27)

An oral delivery system that can be mixed in a normal dry powder process and compressed using a standard tablet making machine:
(A) an effective amount of one or more active ingredients;
(B) one or more polyethylene glycols of molecular weight 1000-8000 or derivatives thereof in an amount sufficient to provide the hardness and time necessary for dissolution of the matrix;
(C) one or more suspending agents of 0.05 to 2% by weight of the total matrix;
Buccal delivery comprising (d) one or more fluidizing agents of 0.05-2% by weight of the total matrix; and (e) one or more sweeteners of 0.05-2% by weight of the total matrix. Provide a system.   The buccal delivery system according to claim 1, wherein the effective amount of the active ingredient is an amount up to about 60% by weight of the total matrix.   The buccal delivery system according to claim 1, wherein the dissolution time of the matrix is within at least 2 hours after administration to the patient.   4. The buccal delivery system according to claim 3, wherein the dissolution time of the matrix is within 40 minutes.   The buccal delivery system according to claim 4, wherein the dissolution time of the matrix is within 12 to 15 minutes.   The buccal delivery system according to claim 5, wherein the dissolution time of the matrix is within 5 minutes.   The buccal delivery system according to claim 1, wherein the buccal delivery system is suitable for sublingual administration.   The buccal delivery system according to claim 1, wherein the buccal delivery system is suitable for sustained release administration.   The buccal delivery system of claim 1, wherein the polyethylene glycol (PEG) is PEG 1450.   The buccal delivery system according to claim 1, wherein the polyethylene glycol (PEG) derivative is a PEG-fatty acid ester having surfactant properties.   Suspending agent is selected from the group consisting of tetragonolobus, Acacia glaucophylla, Acacia abyssinica, Acacia nilotica, Acacia gumifera, and Acacia arabica, remix, a colloidol, The oral delivery system of claim 1, wherein:   Sweeteners include sucrose, sucralose; zinc gluconate; ethyl maltitol; glycine; acesulfame-K; aspartame; saccharin; fructose; xylitol; honey; glycerrizine); dextrose; sodium gluconate; stevia powder; glucono delta-lactone; ethyl vanillin; vanillin; normal and enhanced sweeteners or syrups, or salts thereof, and mixtures thereof, 2. The oral delivery system according to 1.   13. The buccal delivery system of claim 12, wherein the sweetener is a high strength sweetener selected from the group consisting of aspartame, sucralose, and acesulfame-K.   Active ingredients include anti-infectives (antibiotics), eye, ear, nose, and pharyngeal preparations, anti-neoplastics including antibodies, nanobodies, antibody fragments, antibodies for enzyme prodrug therapy (ADEPT), gastrointestinal drugs , Respiratory drugs, joint drugs, blood formation and coagulation drugs, diagnostic drugs, photosensitizers, statins, naproxin, indole-3-acetic acid, hormones and synthetic substrates, cardiovascular drugs, skin and mucosal regulators, NSAIDs, analgesics , Muscle spasms, anti-inflammatory drugs, central nervous system drugs, supplements, diabetes drugs, and electrolytes and water balance agents, mixtures thereof, and their prodrugs, drug complexes, intermediates, enzymes, vitamins, and proteins The buccal delivery system according to claim 1 selected from the group consisting of a complex.   Active ingredients are insulin, triamcinolone, testosterone, levonorgestrel, estradiol, phytoestrogen, estrone, dexamethasone, ethinodiol, prednisone, desogestrel, cryptoterone, norethindrone, megestrol, hydrocortisone, danazol, cortisone acetate, avian, nandrolone, full Oxymesterone, fludrocortisone, fluxoxymesterone, dexamethasone, lebora, fludrocortisone, hypogesterel, methylprednisolone, caton, levonorgestrel, estropipete, levoxil, methimazole, profilthiouracil desmopressin, prednisolone orgestrel・ Norethindrone ・ Triamicinolone ・ Tribora （ selected from the group consisting of rivora), zovia, guestden, alphacalcidol, 1,25-dihydroxyvitamin D3, clomiphene, finasteride, and tibolone, or biologically related intermediates thereof, or combinations thereof 15. An oral delivery system according to claim 14, which is a natural or synthetic hormone.   The buccal delivery system according to claim 1, wherein the active ingredient is a bisphosphonic acid or bisphosphonate salt selected from the group consisting of alendronate, etidronate, pamidronate, tiludronate, and risedronate compounds, and salts thereof.   The oral delivery system of claim 16, wherein the bisphosphonate is alendronate selected from the group consisting of anhydrous alendronate, hydrogenated alendronate salt, and mixtures thereof.   The buccal delivery system of claim 17, wherein the bisphosphonate is alendronate sodium.   The oral delivery system according to claim 16, further comprising one or more hormones used in hormone replacement therapy.   20. The oral delivery system of claim 19, wherein the hormone is selected from the group consisting of estradiol, progesterone, testosterone, dehydroepiandosterone (DHEA), and mixtures thereof.   The buccal delivery system according to claim 1, further comprising one or more other pharmaceutically acceptable carriers and / or excipients.   Pharmaceutically acceptable carriers and / or excipients are binders, flavorings, lubricants, colorants, solubility enhancers, disintegrants, extenders, proteins, cofactors, emulsifiers, solubilizers, complexing 24. The buccal delivery system of claim 21 selected from the group consisting of agents, and mixtures thereof.   The oral delivery system of claim 1, wherein the fluidizing agent is magnesium stearate.   The buccal delivery system of claim 1 further comprising a bound gelling agent.   The oral delivery system of claim 24, wherein the bound gelling agent is hydroxypropylmethocellulose. (A) an effective amount of one or more active ingredients;
(B) one or more polyethylene glycols of molecular weight 1000-8000 or derivatives thereof in an amount sufficient to provide the hardness and time necessary for dissolution of the matrix;
(C) one or more suspending agents of 0.05 to 2% by weight of the total matrix;
(D) a fluidizing agent of 0.05 to 2% by weight of the total matrix; and (e) a sweetener of 0.05 to 2% by weight of the total matrix. An oral preparation prepared by a drying process. A method for producing a dosage formulation capable of delivering one or more active ingredients across one or more membranes in the oral cavity, comprising:
(A) (i) one or more effective amounts of active ingredients;
(Ii) one or more polyethylene glycols or derivatives thereof having a molecular weight of 1000 to 8000 and sufficient to provide the hardness and time required for dissolution of the matrix;
(Iii) one or more suspending agents of 0.05 to 2% by weight of the total matrix;
(Iv) mixing one or more fluidizing agents of 0.05-2% by weight of the total matrix; and (v) one or more sweeteners of 0.05-2% by weight of the total matrix. Preparing the matrix by:
(B) compressing the matrix into a tablet shape suitable for administration to one or more membranes in the oral cavity;
A method wherein the ratio of active ingredient to excipient is such that the active ingredient can be dissolved and absorbed within a desired time.

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